Arginine vasopressin (AVP), a mammalian antidiuretic hormone, and related peptides, when administered exogenously, prolong the duration of tolerance to ethanol. The similarities between neurohypophyseal peptide effects on tolerance and previously reported effects on memory consolidation supported the hypothesis that, as examples of CNS adaptation, these phenomena may share underlying mechanisms. "Environment-dependent" ethanol tolerance results from a conditioned compensatory response to the effects of ethanol, and has a prominent "learned" component. We found that AVP maintains environment-dependent tolerance, consistent with the effects of AVP on learning and memory. However, AVP inhibited the acquisition of environment-dependent tolerance, possibly by interfering with animals' perception of the cues associated with ethanol administration. Initial studies with antagonists of AVP suggested that the endogenous hormone plays a role in maintenance of tolerance. These studies are being extended to examine the effects of antagonists specific for V1 and V2 vasopressin receptors, in order to characterize the CNS receptors that mediate hormonal effects on tolerance. The role of endogenous AVP is also being investigated through studies of the biosynthesis of AVP (including levels of mRNA, precursor molecules, and hormone itself) during chronic ethanol exposure leading to tolerance development. Understanding the role of the peptide hormones in development, expression and dissipation of various forms of tolerance to ethanol may lead to benign means for the manipulation of the development of tolerance and, possibly, of ethanol intake.